Zn-DHM nanozymes regulate metabolic and immune homeostasis for early diabetic wound therapy

Diabetic wounds heal slowly or incompletely because of the microenvironment of hyperglycemia, high levels of reactive oxygen species (ROS), excessive inflammation, metabolic disorders and immune dysregulation, and the therapeutic effect is limited only by disruption of the reactive oxygen species (ROS)-inflammation cascade cycle. Here, a novel metal-polyphenolic nanozyme (Zn-DHM NPs) synthesized by the coordination of Zn 2+ with dihydromyricetin (DHM) was designed, which not only has a superior ability to scavenge ROS and promote cell proliferation and migration but also functions in the regulation of metabolism and immune homeostasis. In vitro and in vivo experiments and RNA sequencing analyses revealed that Zn-DHM NPs could increase the levels of intracellular SOD and CAT enzymes to scavenge ROS and maintain the level of the mitochondrial membrane potential to reduce apoptosis. In terms of glucose metabolism, Zn-DHM NPs downregulated excessive levels of intracellular glucose and HK2, inhibited excessive glycolysis and downregulated the AGE-RAGE pathway to restore cellular function. In terms of immune regulation, Zn-DHM NPs not only downregulate M1/M2 levels to promote tissue repair but also maintain Th17/Treg homeostasis, downregulate the IL-17 signaling pathway to reduce inflammation, and upregulate FOXP3 to maintain immune homeostasis, thereby promoting early wound healing in diabetic mice. The development of Zn-DHM NPs provides a new therapeutic target to promote early healing of diabetic wounds. • Zn-DHM NPs attenuate HG-induced oxidative stress and protect mitochondrial function, the ROS‒inflammation cascade cycle can be effectively disrupted. • Excessive levels of intracellular glucose and HK2 were downregulated, and the production of excessive glycolytic products (lactic acid) and glucose metabolism intermediates (AGEs) was inhibited, the HG-induced disorders of glucose metabolism were regulated. • The M1/M2 level is downregulated to reduce the release of inflammatory factors, and tissue repair is promoted. The homeostasis of Th17/Treg levels is maintained, which reduces inflammation and promotes wound remodeling. In addition, the differentiation of naive CD4 + T cells into Tregs is increased, which upregulates the FOXP3 factor to maintain immune homeostasis.